The epithelial tissues of the human oral cavity are constantly exposed to a variety of microbial challenges that lead to bacterially induced periodontal diseases and other infections. Recent findings point to mucosal epithelial cells as the sources of microbicidal agents, belonging to a family of small, cationic peptides. These molecules, primarily human beta-defensins 1 and 2 (hBD-1, hBD-2), and FALL39, a cathelin class peptide, are predicted to function as a first line of host defense against microbial pathogenesis. We have discovered that these peptides are expressed in normal human gingival epithelial cells, and that the beta-defensins are upregulated by Fusobacterium nucleatum. Surveillance through gingival epithelial cell antimicrobial peptides (GAPs) may function to keep the natural flora in a steady state in different niches of the human body, including the oral cavity. This proposal intends to test hypotheses emanating from the postulate that oral epithelial cells can be stimulated to produce beta-defensins that protect the host from bacterial challenges at the oral mucosal barrier. The objectives of this proposal are (1) to determine the kinetics of beta-defensin expression in gingival epithelial cells in response to challenge with F nucleatum, (2) to test components of F. nucleatum that may regulate expression of beta-defensins, and (3) to examine if beta-defensins elicit protection against oral bacteria. This proposal offers the hypothesis that the evolutionarily ancient peptide-based antimicrobial defense found in mammalian mucosal membranes may be an extremely important way by which the gingival epithelium resists invasion of potentially noxious microorganisms. In light of the frequent adjunctive use of antibiotics in treating oral diseases, with the threat of microbial resistance, investigations into novel eukaryotic peptides, such as gingival antimicrobial peptides, are highly significant and offer the potential for future clinical promise. This novel research direction is viewed as extremely significant in leading to future studies that have potential application to oral disorders and may have some transfer to clinical applications and technology development.